Differentiated Thyroid Carcinoma Long-Term Prognostic Factors

Introduction Thyroid cancer is the most common cancer in women in Ecuador. Objective The aim of this study was to determine the demographics and clinical and treatment variables of patients with papillary or follicular thyroid cancer, referred to as differentiated thyroid cancer (DTC), treated at a third-level hospital in Quito, Ecuador. Methods We reviewed retrospectively the medical records of patients with DTC, who underwent surgical treatment, from 1990 to 2019. Data included demographics, pathological information, clinical stage, type of surgery, and radioactive iodine (RAI) adjuvant therapy. Patients were monitored for up to 29 years (median follow-up time 6.9 years). Results The corrected overall 5-, 10-, 20-, and 30-year survival rates (Kaplan–Meier) were 93%, 85%, 70%, and 63%, respectively. On univariate analysis, age, histological type, tumor grade, histological variants, capsular invasion, vascular invasion, tumor size, clinical stage, distant metastases at diagnosis, surgical margins, extrathyroidal invasion, radioactive iodine adjuvant treatment, and locoregional recurrence were found to be significant prognostic factors. In a multivariate analysis, the following independent variables: age over 55 years, extrathyroidal spread, metastasis at diagnosis, and stage II to IV raised the risk of death (hazard risk) (HR). Conclusions Age over 55 years, extrathyroidal spread, metastasis at diagnosis, and advanced clinical stage were found to have a harmful prognosis and an increased risk of death in a series of Ecuadorian patients surgically treated for a DTC.


Introduction
Tyroid cancer is the commonest endocrine malignancy.A steadily increasing incidence has been observed in developed as well as developing countries [1].In the United States, in 2018, the incidence in men and women was 3.4 and 10.1 per 100.000inhabitants, respectively.In Ecuador, the current incidence is 8.2 and 40.9 for both sexes [2].Tis incidence in Ecuadorian women is the ffth highest in the world.On the other hand, mortality in men and women has remained low: 0.34 and 0.48 per 100.000inhabitants in the United States [1] and 1.1 and 2.7, respectively, in Ecuador [2].
Prognostic factors have been intensively studied since the 1980s.To predict outcomes and select individualized treatment, numerous staging classifcation systems were proposed such as AMES, GAMES, and MACIS.Te American Tyroid Association (ATA) published in 2016 an initial risk stratifcation system for thyroid carcinoma (DTC) utilizing prognostic factors such as histologic type, pathology characteristics, and mutational status to assist the decision-making for radioactive I 131 adjuvant treatment [3].
Te aim of this study was to determine the predictive of demographics and clinical and treatment variables of patients with papillary or follicular thyroid cancer, referred to as diferentiated thyroid cancer (DTC), treated at a thirdlevel hospital in Quito, Ecuador, South America.

Materials and Methods
We reviewed retrospectively the medical records of patients with DTC, who underwent surgical treatment, from 1990 to 2019 at a tertiary public hospital in Quito, Ecuador.All patients signed an informed consent before surgery.Te hospital's ethics committee permission was obtained.Data included demographics, pathological information, clinical stage, type of surgical procedure, and radioactive iodine (RAI) adjuvant therapy.Patients were followed up to 29 years with a median time of 6.9 years.Pathological diagnoses and clinical staging were based on the Protocol for the Examination of Specimens from Patients with Carcinomas of the Tyroid Gland of the American College of Pathologists and the AJCC [4,5].

Statistical Analysis.
Continuous variables are summarized as mean ± SD and categorical variables as percentages.Age was divided into two groups, age ≤55 years and age >55 years.Patients were stratifed by using the TNM staging criteria.
To assess survival rates, we employed the univariate analysis with Kaplan-Meier and the log-rank test to compare two or more survival curves of unadjusted overall survival between categorical variables and death.For multivariate analysis, we used the semiparametric Cox proportional hazards model to identify risk factors for mortality.P value with a signifcance level set at P < 0.05, adjusted hazard ratio (HR), and 95% confdence interval (CI) are also reported.
Te best-ftting Cox proportional hazards model was selected using the Akaike information criteria (AIC).Te fnal model had only four covariates that satisfed the proportionality hazard assumption, namely, age over 55 years, carcinoma stage, compromised margins, and extrathyroidal extension.Te model was assessed with Schoenfeld's global test to assess the proportional hazards assumption in the Cox model.
Seventeen features considered for univariate analysis of survival are shown in Table 2. Sclerosing, tall cells, columnar cells, and insular carcinomas were considered aggressive histological variants.
On univariate analysis, age, histological type, tumor grade, histological variants, capsular invasion, vascular invasion, tumor size, clinical stage, distant metastases at diagnosis, surgical margins, extrathyroidal invasion, radioactive iodine adjuvant treatment, and locoregional recurrence were found to be signifcant prognostic factors.

Cox Proportional Hazards Model.
In the multivariate analysis, Cox PH model, beta regression coefcients from all covariates included in the model reached a high statistical signifcance.Tough, having death as the dependent variable, the independent variables such as age over 55 years, extrathyroidal spread, the presence of metastasis at presentation and stage II to IV tumors of the thyroid cancer raised the hazard risk of death (HR) (Figure 1).Te exponentiated coefcients or hazard ratios of those covariates gave us the efect size.On the other hand, the global signifcance of the model tested by asymptotically equivalent tests such as the Schoenfeld global test, likelihood ratio, Wald test, and score log-rank statistics confrmed model signifcance.
Since the requirement of the Cox PH model is the inclusion of covariates in the dataset that satisfy the proportional hazard (PH) assumption, we used the Schoenfeld residual test in RStudio to make sure that regression parameters were constant over time.Covariates that did not satisfy the PH assumption were excluded from the fnal Cox PH model.Results from this analysis are presented in Table 3.
According to the hazard ratio obtained, patients with thyroid carcinoma older than 55 years old, at a given instant in time are 3.32 times as likely to die as those who are younger than 55 years old, while keeping constant other explicative variables (p < 0.0001).Using the Akaike information criteria (AIC), the best-ftting Cox PH model had the four covariates that ft the proportional hazard Cox model assumptions.Te histological type of thyroid cancer, compromised margins, lymph node involvement, tumor size, and type of surgery neither reached signifcance nor improved the model prediction, therefore, those variables were excluded.Meanwhile, age, thyroid cancer stage, and metastasis plus extrathyroidal extension did ft the model and they were selected by stepwise approach.Te thyroid carcinoma stage IV patients had a HR � 6.19, 95% CI (1.09-35.04),and p � 0.05 of worse survival compared to patients in stage I adjusted to other covariates.

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International Journal of Surgical Oncology By contrast, the follicular type of cancer that in the univariate analysis had a worse prognosis than papillary carcinoma, once included in the model and holding the other covariates constant, their p value was not signifcant.
Having ft a Cox model to the data, we visualized the predicted survival proportion at any given point in time for a particular risk group and estimated the survival proportion, at the mean values of covariates.Te following plot shows a fairly good predicted survival probability for our series of thyroid cancer patients surgically treated and followed up longer than 40 years (Table 4).

Discussion
DTC has a good prognosis in most cases.However, some patients may have some characteristics that can determine an adverse outcome.
Even if age, histological type, tumor grade, histological variants, capsular invasion, vascular invasion, tumor size, clinical stage, distant metastases at diagnosis, surgical margins, extrathyroidal invasion, radioactive iodine adjuvant treatment, and locoregional invasion were found to be signifcantly prognostic by univariate analysis, only age >55 years, extrathyroidal spread, the presence of metastasis at diagnosis, and tumors stratifed into stages II to IV of the AJCC Staging Classifcation System remained as independent signifcant prognostic factors by multivariate analysis in the present study.
In a recent series of 422 thyroid cancer cases, age, initial lymph node involvement, number of radioiodine therapies, and histopathology of the tumor were selected as independent signifcant predictors for mortality [7].Te most unfavorable factors of the prognosis for patients with DTC in a series of 5526 patients reported by Guda [8] were stage IV A and age older than 60.Other prognostic factors (multifocal tumor growth, lymph node involvement, male sex, and recurrence) were also predictive factors, but with a somewhat less signifcance.
In another series of 6015 papillary thyroid carcinoma reported by Ito [9], the important prognostic factors were age 55 years or older, distant metastasis at surgery, clinical lymph node metastasis measuring 3 cm or larger, extranodal tumor extension, and signifcant extrathyroidal extension.Tumors larger than 4 cm, clinical node metastasis smaller than 3 cm with no extranodal tumor extension, and male gender were moderate prognostic factors.In this large series report, on multivariate study, age at 55 years or older was the most signifcant prognostic factor for cause-specifc survival (CSS), except for distant metastasis at surgery [9].Age was a signifcant independent prognostic factor, by multivariate analysis, in the present series.
Regarding tumor histology, the 10-year survival for papillary thyroid cancer (PTC) is around 95% and for follicular thyroid cancer (FTC), 70 to 95%.Tis slightly worse survival for FTC has been described to be possibly due to later presentation and the presence of distant metastases at diagnosis [10].Even if PTC had a signifcantly better prognosis in our patients, by univariate analysis, it was not confrmed by multivariate analysis in the present series.In a systematic review with meta-analysis, Kim [11] found that multifocality was signifcantly associated with an increased risk of recurrence, while cancer-specifc survival showed no diference.In subgroup analyses, the hazard ratios of multifocality for recurrence were associated with primary tumor size (1.81 and 1.90 for 1 cm versus >1 cm, respectively), number of tumor foci (1.45 and 1.95 for 2 foci versus 3 foci, respectively), and patient age (HRs for  International Journal of Surgical Oncology pediatric and adult patients were 3.19 and 1.89 for pediatric versus adult patients, respectively).Multifocality was not a signifcant prognostic factor in our study.Te presence of tumor capsular invasion has appeared not to have signifcance for the long-term prognosis of patients with PTC or FTC since early studies [12].Encapsulated tumors with microscopic capsular invasion are currently considered as minimally invasive [3].On the other hand, a recent meta-analysis demonstrated a signifcant impact of vascular invasion on tumor recurrence and patient survival in DTC patients [13], so the authors recommended considering the presence and extent of vascular invasion as an adverse prognostic factor in DTC.In a large study with patients registered in the National Cancer Database of the United States of America [14], it was demonstrated that the presence of lymphovascular invasion among patients with PTC was independently associated with compromised overall survival.It was concluded that these patients should be considered at higher risk, and adjuvant RAI should be more strongly considered.In our study, on univariate analysis, vascular invasion appeared as a very signifcant prognostic factor, capsular invasion had only mild signifcance, and lymphatic invasion was not signifcant.
Te combined aggressive pattern carcinomas, when compared with the other variants, classical and follicular, had a higher risk of invasion of the thyroid capsule invasion, lymphovascular invasion, extrathyroid invasion, and lymph node metastasis.Tese aggressive variants are also associated with higher rates of recurrence and metastasis and may have lower survival rates [15].In a large multi-institutional study including 91,145 patients from the National Cancer Database, Khokar [16] reported that tall cell variants had worse overall survival than classical and difuse sclerosing variants which had both similar survivals.In another recent large study, Xu [17] reported a signifcantly highest 5 year overall and disease-specifc survival for the follicular variant, followed by the conventional variant and by tall cell variant.
Staging is important not only to predict outcomes but also to facilitate treatment decision-making [18].In the present study, we found, by multivariate analysis, that stages II to IV signifcantly raised the risk of death.Stage I (microcarcinoma, <1 cm in size) patients had an excellent 95% 10-year survival.
Distant metastasis at diagnosis is one of the most important prognostic factors for cause-specifc survival (CSS) of patients.Tey are more likely found in patients showing aggressive behavior and directly linked to other clinicopathological features such as gender, tumor size, and extrathyroidal extension [9].In our study, distant metastases at the time of diagnosis appeared to be an independent prognostic factor, by multivariate analysis.
Recent data have demonstrated that in properly selected patients, clinical outcomes are very similar following unilateral or bilateral thyroid surgery [3,10].Our fnding that the partial and total thyroidectomy do not difer signifcantly in survival would indicate that a more adapted surgical procedure based on tumor size end extent and lymph node involvement is required.
A meta-analysis based on six studies with 7696 patients did not fnd a statistically signifcant association between microscopically positive surgical margins and local recurrence.So, a fnding of microscopically positive surgical margin in the absence of other adverse factors would not be an indication for adjuvant treatment [19].However, there is controversy regarding the prognostic value of microscopic extrathyroidal tumor extension (MEE) [20].Positive surgical margins were not a prognostic factor in our study.
Macroscopic extrathyroidal extension on intraoperative evaluation is an important factor in predicting a worse prognosis for patients with PTC.However, three categories of this extension, each with a diferent prognosis, were defned in the 8 th edition of the AJCC staging system: T3b tumors, invading only the strap muscles; T4a tumors invading subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve; and T4 tumors invading the prevertebral fascia or encasing the carotid artery or mediastinal vessels [5].In our study, extrathyroidal extension was an important prognostic factor by multivariate analysis.
Multiple studies have reported no association between regional lymph node metastases and overall survival but a consistent correlation with local recurrence has been described [7,18,[21][22][23].We did not fnd a statistical infuence of pathologically positive lymph nodes on survival.
Te use of I131 treatment after thyroidectomy improves clinical outcomes in terms of recurrence and survival in selected patients with DTC.Tis beneft has been observed in advanced disease stages but not in small primary tumors [10].According to the ATA guidelines, RAI remnant ablation after thyroidectomy is not recommended for low-risk DTC patients, and it should be considered for intermediate-risk patients and recommended to high/risk patients.Even if RAI adjuvant International Journal of Surgical Oncology treatment improved survival in the whole cohort of patients in our series, by univariate analysis, it was not found efective by multivariate analysis.
Te impact of locoregional recurrences on the long-term survival of patients with PTC has been rarely discussed in the literature.In the present series, patients with locoregional recurrences had a signifcantly compromised overall survival.In a study with data collected from 1636 subjects with PTC at National Taiwan University Hospital [24], the locoregional recurrences had a moderately harmful impact on overall and disease-specifc survival.
An analysis of the prognostic impact of other demographics [25], pathological, clinical, and therapeutic variables, as well as the study of the infuence of additional factors within each variable, analyzed in the present cohort of patients, is warranted in the future.
One strength in this series is that follow-up was performed in all our patients, even if it was not long enough in a group of them, a fact that is difcult to obtain in Latin America.Only a few studies in this region had included follow-up results [26,27].However, limitations include the retrospective nature of the study and the lack of digital data in the patients treated in the frst years of this study.

Conclusions
Overall long-term survival of a series of Ecuadorian patients with DTC and surgically treated has been as good as in all reported data.However, some factors such as an age >55 years old, extrathyroidal spread, the presence of metastasis at diagnosis, and advanced clinical stage were found to have a less good prognosis and an increased risk of death, by multivariate analysis.

Figure 1 :
Figure 1: Overall survival according to clinical stage.

Table 1 :
Demographic and clinical characteristics of the population.

Table 2 :
Overall survival by univariate analysis.

Table 3 :
Risk factors for mortality in thyroid cancer.